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Journal of Medical Microbiology logo Journal of Medical Microbiology

Volume 74, Issue 6

Hantaan virus activates Src family kinase and induces endothelial cell hyperpermeability via the TLR4/TRAF6 pathway Open Access

Abstract

Hantaan virus (HTNV) predominantly infects human vascular endothelial cells (ECs) and causes increased vascular permeability, triggering haemorrhagic fever with renal syndrome, mainly in Asia. Previous studies have shown that endothelial permeability is regulated in part by the break of cell–cell adherens junctions (AJs). However, the intracellular mechanisms by which HTNV induces EC hyperpermeability via AJs remain unclear.

We hypothesize that HTNV activates TLR4, and its downstream TRAF6 interacts with SFK, leading to the phosphorylation of adhesion junction-associated proteins and increased cell permeability.

The present study aimed to investigate the molecular mechanism by which Src family kinases (SFKs) modulate AJs and affect permeability.

Real-time PCR (RT-PCR) and Western blot were used to assess TLR4, TRAF6 and SFK expression; Western blot was used to analyse the protein expression of AJs; small interfering RNAs (siRNAs) were used to inhibit gene expression in the human umbilical vein endothelial cells (HUVECs) and the distribution of vascular endothelial cadherin (VE-cadherin) was observed by immunofluorescence.

HUVECs infected by HTNV displayed a lower permeability after a siRNA knockdown of TLR4 (si-TLR4). Moreover, HTNV increased the expression of TRAF6 and the phosphorylation of Src and AJs. After siRNA knockdown of TRAF6 (si-TRAF6), a decrease in the phosphorylation of Src and VE-cadherin was observed in HTNV-infected ECs compared to that in siRNA controls.

These data, for the first time, indicated that HTNV-induced upregulation of AJ phosphorylation is regulated by the TLR4/TRAF6/SFK signalling pathway.

  • Received:
  • Accepted:
  • Published Online:
Keyword(s): endothelial cells , haemorrhagic fever with renal syndrome , Hantaan virus , Src family kinase , toll-like receptor 4 and vascular endothelial cadherin (VE-cadherin)
Funding
This study was supported by the:
  • Social Talent Fund Support Programme of Tangdu Hospital (Award 2021SHRC058)
    • Principle Award Recipient: ZhangYing
  • Key Research and Development Programme of Shaanxi Province (Award 2023-ZDLSF-32)
    • Principle Award Recipient: ZhangYing
  • Natural Science Foundation of China (Award 81373118)
    • Principle Award Recipient: YingZhang
© 2025 The Authors
  • This is an open-access article distributed under the terms of the Creative Commons Attribution License.
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2025-06-02
2025-06-13
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/content/journal/jmm/10.1099/jmm.0.001989
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Hantaan virus activates Src family kinase and induces endothelial cell hyperpermeability via the TLR4/TRAF6 pathway
J. Med. Microbiol. 74, 001989 (2025); https://doi.org/10.1099/jmm.0.001989
/content/journal/jmm/10.1099/jmm.0.001989
/content/journal/jmm/10.1099/jmm.0.001989
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